This is a renewal of a program previously entitled "Cholinergic Treatment of Memory Deficits in the Aged". That program helped to develop the rationale, methods, and preliminary data for many of the large multi-site clinical trials, of potential treatments for Alzheimer's Disease (AD) which are now being supported by NIH and the pharmaceutical industry. The current proposal is designed to fill a major gap in our understanding of AD resulting from the fact that the great majority of clinical and biologic studies of AD involve patients with established and often advanced disease. Further advances in the diagnosis, treatment and prevention of AD will benefit greatly from a better understanding of the earliest biological and clinical changes in AD. The current proposal includes 5 scientific projects investigating persons at high risk for AD and comparing them with demographically matched groups of normal controls and AD patients. The groups to be studied longitudinally are: cognitively normal elderly, AD, AD, and elderly first degrees relatives of AD probands. A high proportion of persons in all groups except the first degree relatives will coke to autopsy during the 5 years of the proposed program. Project 1 will involve all groups and will test hypotheses about the neuropsychological changes in early AD will be tested using autopsy material in projects 3 and 5, respectively. Project 2 will test hypotheses about demographic factors, particularly age of onset, that may be associated with a greater genetic contribution to the development of AD. Project 4 will determine whether acute phase reactants, which are elevated in serum of some AD patients and some first degrees relatives are early indicators of AD and whether they are specific for amyloidogenic conditions. The ultimate aim of the program is to improve the diagnosis and treatment of AD through a better understanding of it's earliest manifestations.